Methods:
We conducted a genome-wide association study in 1404 severe FECD cases and 2564 controls of European ancestry using the Illumina Omni 2.5 chip. After imputing our markers to the 1000 Genomes, the primary analyses consisted of association testing via logistic regression, controlling for population structure via six principal components, and covariates age and sex. Genome-wide significant markers at six loci were validated in three independent replication samples (N=671 cases and N=778 controls) via a fixed-effects meta analysis. We also conducted sensitivity analysis for histopathology validated cases, and determined whether female versus male gender showed differences in odds ratios at the best loci. Genetic risk scores were calculated based on the most significantly associated SNP from each of the four replicated regions (AUC).

Conclusions:
The FECD Genetics Consortium has conducted the largest genome-wide association study to date on FECD, leading to confirmation of the role of TCF4 on FECD, and identification of three novel validated loci. Further analyses of these genes should help elucidate different pathways in FECD pathogenesis.